title: [PARP inhibitors for cancer therapy].
abstract: Poly(ADP-ribose)polymerases(PARPs)can transfer their first ADP-ribose moiety from nicotinamide adenine dinucleotide( NAD+)to an acceptor protein. PARPs play a major role in a wide range of biologic processes through poly(ADP-ribosyl) ation, including the maintenance of genomic stability, transcriptional regulation, energy metabolism, and cell death. Recent findings have thrust(PARPs)into the limelight as potential chemotherapeutic targets, and PARP inhibitors(poly(ADP-ribose) polymerase inhibitors)are currently undergoing clinical evaluation for use as new anti-cancer drugs. PARPs promote the repair of single-strand breaks(SSB)by base excision repair(BER), and the inhibition of PARPs leads to the conversion from single-strand breaks(SSB)to double-strand breaks(DSB). Because BRCA1- or BRCA2-deficient cells are unable to complete homologous recombination efficiently, PARP inhibition in these cells causes a high degree of genomic instability and eventual cell death termed synthetic lethality. This synthetic lethal approach has been validated in studies that show a striking single-agent activity of PARP inhibitors in preclinical models of BRCA1 and BRCA2 inactivation. Consistent with these results, the PARP inhibitor olaparib(previously known as AZD2281)has shown promising single-agent activity against it in early clinical testing. In additional studies, the PARP inhibitor has shown remarkable activity in BRCA1- or BRCA2-mutant tumors when used in combination with gemcitabine and carboplatin. Phase I and Phase II trials of several PARP inhibitors in combination with DNA-damaging agents are ongoing.
authors.affiliation: Dept. of Molecular Diagnosis, The Cancer Institute of JFCR, Medical Research Institute, Tokyo Medical and Dental University, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Saito
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Miki
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases